US5427958A - Synthetic peptides of the conjugate of ubiquitine and H2A histone - Google Patents
Synthetic peptides of the conjugate of ubiquitine and H2A histone Download PDFInfo
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- US5427958A US5427958A US07/655,437 US65543791A US5427958A US 5427958 A US5427958 A US 5427958A US 65543791 A US65543791 A US 65543791A US 5427958 A US5427958 A US 5427958A
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the object of the present invention is peptides that can be recognized by antibodies in biological fluids, in particular serums in patients or animals stricken with auto-immune diseases such as systemic Lupus Erythematosus or diseases of the nervous systems such as Alzheimer's or Parkinson's diseases.
- the invention also concerns applications of these peptides and compositions containing them in in vitro diagnoses in man of the potentiality of certain auto-immune or nervous-system diseases, as well as their use in diagnostic kits.
- the invention further concerns the application of these peptides in the production of immunogenic compositions and of vaccines used against these diseases.
- the invention concerns antibodies that can be induced in vivo by these immunogenic peptides and compositions which contain them used for in vitro diagnosis in patients stricken with auto-immune or nervous-system diseases, as well as the manufacture of medications used against these diseases.
- ubiquitine may be present in cells both in the free state and united with a large number of proteins of the nucleus, the cytoplasm, or the membrane, or may also be linked to the network of microtubules.
- the conjugates of ubiquitine of the cytosol are known to be selective mediators of the breakdown of damaged or abnormal proteins.
- H. Busch et al. Molec. Cell. biol., 3:1, 1981
- A. W. Thorne et al. EMBO J., 6:1005, 1987
- ubiquitine is enzymatically conjugated with histones by means of a peptide bond between the group ⁇ -COOH of the C-terminal glycine in position 76 of the ubiquitine and the group--NH2 of the lateral lysine chain in position 119 in the H2A histone and in position 120 in the H2B histone, thus forming branched molecules.
- H2A and H2B histones conjugated with ubiquitine are present in the proportions of 10% and 1%, respectively.
- Antiserums of animals immunized with these peptides react specifically with the conjugate of the ubiquitine and of the H2A histone, and not with the H2A histone and/or with the free ubiquitine. Furthermore, the serums of patients stricken with Systemic Lupus Erythematosus reacting immunologically with the ubiquitine also react with these peptides.
- peptides are thus applicable to the diagnosis of Systemic Lupus Erythematosus and more broadly, to all autoimmune or nervous system diseases in which the conjugate of ubiquitine with the H2A histone plays a role.
- the peptides according to the invention have immunological properties in common with the peptide corresponding to the following formula: ##STR1##
- peptides preferred according to the invention have the following formula: ##STR2## in which:
- X and Y represent either an NH2 group which is free or in which amide is introduced by one or two alkyl groups comprising from 1 to 5 carbon atoms, or a peptide group containing from 1 to 10 amino acid residues, in which the N-terminal amino acid has a free or amide-containing NH2 group, as before.
- Z represents either a free or alkoxyl OH group which then contains an alkyl group comprising 1-5 carbon atoms, or a peptide group containing 1-10 amino acid residues, in which the C-terminal amino acid had a free or alkoxyl OH group, as before.
- the groups comprising 1-10 amino acid residues contained in X and/or Y and/or Z are selected essentially so as to preserve the immunological properties of the peptide corresponding to formula (I).
- the sequence Gly-Gly-Arg-Leu corresponds to the fraction of the ubiquitine sequence
- the Lys-Lys-Thr-Glu sequence corresponds to the fraction of the H2A histone sequence at the branching point between these two compounds in the conjugate of the ubiquitine with the H2A histone.
- the groups containing 1-10 amino acid residues contained in X and/or Y and/or Z may, in particular, correspond to the adjoining amino acids of the peptide corresponding to formula (I) in the ubiquitine-H2A histone conjugate.
- Y represents either a free NH2 group or a Tyr residue containing a free NH 2 group
- X represents a Cys residue whose amine function can possibly be acetylated
- Z represents an OH group.
- Y represents either a free NH2 group or a Tyr residue containing a free NH 2 group
- X represents the linking of the two Leu and Pro residues, the Pro residue being linked by a peptide bond to the adjacent Lys residue of X in formula (II) and the amine function of the Leu residue being possible acetylated
- Z represents an OH group.
- the invention specifically focuses on peptides corresponding to the following formulae: ##STR3## in which the amine function of the Leu residue is acetylated (AC); and ##STR4## in which the amine function of the Cys residue is acetylated (Ac).
- the invention concerns peptides which are modified by the insertion and/or deletion and/or substitution of one or several amino acids, as long as the antigenic or immunogenic properties of said peptides are not modified, as well as those in which the peptide bond (--C--NH--) is replaced, for example, by the following structures: --CO--N(CH 3 )--, --CH 2 --CH 2 --, --CO--CH 2 --, or again, in which the peptide skeleton has one or several inserted groups such as the groups --CH 2 --, --NH--, or --O--.
- the present invention also encompasses peptides in which the amino acid residues having an asymmetrical carbon are in the form of D or L.
- the peptides according to the invention may be prepared using conventional techniques involving peptide synthesis in the solid phase, either by the successive condensation of the amino acid residues in the required order, or by condensation of the amino acid residues on a previously-formed fragment which contains several amino acids in the suitable order, or, yet again, by condensation of several previously-prepared fragments, taking care to preliminary protect all of the reactive functions borne by the amino acid residues or fragments, except for the amine and carboxyl functions involved in the peptide bond formed during condensation.
- the Glu residue whose amine function is protected by a terbutyloxycarbonyl group
- the second amino acid residue is linked in dimethylformamide.
- the amino acid residues are fixed one after the other, these residues forming the portion of the peptide according to the invention which corresponds to the fraction of the H2A histone sequence.
- the amine function of the N-terminal residue can be acetylated under the effect of an excess of acetic anhydride in the presence of diisopropylethylamine.
- the lateral chains of the trifunctional amino acids must be protected, for example by using the following groups: cyclohexyl for glutamic acid, benzyl for threonine, tosyl for arginine, paramethylbenzyl for cysteine, 2,6-dichlorobenzyl for tyrosine, fluorenylmethyloxycarbonyl for one of the lysines and 2-chlorobenzyloxycarbonyl for the other lysine.
- the lateral chain of the lysine on which branching occurs is advantageously protected by a fluorenymethoxycarbonyl group.
- the first glycine residue corresponding to the fraction of the ubiquitine sequence is linked as before.
- the amino acids which will form the peptide chain are gradually linked on the amine group whose protection is preliminarily removed on each occasion, the portion already formed remaining attached to the resin.
- the peptide according to the invention is removed from the solid substrate, for example using hydrofluoric acid.
- the raw product is lyophilized and undergoes chromatography in the liquid phase under medium pressure, thus making it possible to obtain a product whose purity reaches approximately 93%. This latter is then characterized by using chromatography in the liquid phase under high pressure and by analyzing its amino acid composition and by mass spectrometry.
- the invention also concerns the conjugates obtained by linking peptides according to the invention to carrier molecules which may be physiologically acceptable and non-toxic.
- the peptides corresponding to formula (II), in which Y represents a Tyr residue may advantageously be linked to a carrier protein using bis-diazobenzidine.
- the peptides corresponding to formula (II) in which X represents a Cys residue may be linked to a carrier molecule or to a substrate by means of a thiol group.
- carrier molecules natural proteins such as tetanic formol toxoid, albumin, or serum albumins may be mentioned.
- the invention also concerns the peptides according to the invention marked using a suitable marker, for example biotin or its derivatives, an enzyme like peroxidase, a fluorescent marker like fluorescein, a radioactive marker such as a radioisotope, etc.
- a suitable marker for example biotin or its derivatives, an enzyme like peroxidase, a fluorescent marker like fluorescein, a radioactive marker such as a radioisotope, etc.
- the invention further concerns antibodies formed against peptides according to the invention.
- These antibodies may be polyconal or monoclonal, and are thus produced by any hybridoma prepared according to conventional methods for producing cellular fusion between the splenic cells of an animal immunized against any of the invention peptides and cells from a line of myeloma cells.
- Rabbit antiserums have been prepared based on the formula (IV) peptide linked to ovalbumin.
- the antibodies obtained react with neither ubiquitine not the H2A histone during immunoenzymatic ELISA-type tests. Using immunotransfer techniques, these antibodies have made it possible to show that contaminating fractions having atomic mass numbers of 43 and 52 kilodaltons corresponded to ubiquitine-H2A histone conjugates.
- the antibodies prepared using these peptides constitute very specific probes of the ubiquitine-H2A histone conjugates which are incapable of binding free ubiquitine or H2A histone.
- the antibodies according to the invention make it possible to identify the conjugate unequivocally.
- the antibodies formed against the invention peptides and the auto-antibodies of patients which react with said peptides and obtained after affinity chromatography can be used to prepare anti-idiotype antibodies partially forming an exact copy of the initial antigenic peptide, and which are, therefore, capable of bonding with the auto-antibodies observed in auto-immune diseases.
- the present invention also concerns these anti-idiotype antibodies and compositions containing them, as well as their application in the in vitro diagnosis in man of the presence of auto-antibodies and the production of medications used to combat these auto-immune diseases.
- the invention also concerns immunogenic compositions used to produced vaccines whose active agent is formed by at least one peptide or one anti-idiotype antibody according to the invention which, possibly linked to a carrier molecule, leads to the production of antibodies against said peptides and which are capable of interfering with the pathology and/or clinical manifestations of the auto-immune diseases.
- the pharmaceutical compositions according to the invention which may be used as vaccines, are made up of solutions or suspension which can be injected or administered by other means and can be administered in doses of between 10 ⁇ g/kg and 100 mg/kg of peptides according to the invention.
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- Medicinal Chemistry (AREA)
- Genetics & Genomics (AREA)
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- Proteomics, Peptides & Aminoacids (AREA)
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- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
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Abstract
Description
______________________________________ Ala alanine Cys cysteine Asp aspartic acid Glu glutamic acid Phe phenylalanine Gly glycine His histidine Ile isoleucine Lys lysine Leu leucine Met methionine Pro proline Ser serine Thr threonine Val valine Trp tryptophane Tyr tyrosine. ______________________________________
Claims (4)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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US08/418,435 US5545718A (en) | 1989-04-26 | 1995-04-07 | Synthetic peptides of the conjugate of ubiquitine and H2A histone |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR8905531A FR2646425B1 (en) | 1989-04-26 | 1989-04-26 | SYNTHETIC PEPTIDES OF THE CONJUGATE OF UBIQUITINE AND HISTONE H2A |
FR8905531 | 1989-04-26 | ||
PCT/FR1990/000288 WO1990012806A1 (en) | 1989-04-26 | 1990-04-23 | Synthetic peptides of the conjugate of ubiquitine and histone h2a |
Related Child Applications (1)
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US08/418,435 Division US5545718A (en) | 1989-04-26 | 1995-04-07 | Synthetic peptides of the conjugate of ubiquitine and H2A histone |
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US5427958A true US5427958A (en) | 1995-06-27 |
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US07/655,437 Expired - Fee Related US5427958A (en) | 1989-04-26 | 1990-04-23 | Synthetic peptides of the conjugate of ubiquitine and H2A histone |
US08/418,435 Expired - Fee Related US5545718A (en) | 1989-04-26 | 1995-04-07 | Synthetic peptides of the conjugate of ubiquitine and H2A histone |
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US08/418,435 Expired - Fee Related US5545718A (en) | 1989-04-26 | 1995-04-07 | Synthetic peptides of the conjugate of ubiquitine and H2A histone |
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US (2) | US5427958A (en) |
EP (1) | EP0423301B1 (en) |
JP (1) | JPH03505590A (en) |
DE (1) | DE69006306T2 (en) |
FR (1) | FR2646425B1 (en) |
WO (1) | WO1990012806A1 (en) |
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WO2003086273A2 (en) * | 2002-04-08 | 2003-10-23 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Histone conjugates and uses thereof |
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-
1989
- 1989-04-26 FR FR8905531A patent/FR2646425B1/en not_active Expired - Fee Related
-
1990
- 1990-04-23 EP EP90907150A patent/EP0423301B1/en not_active Expired - Lifetime
- 1990-04-23 JP JP2507382A patent/JPH03505590A/en active Pending
- 1990-04-23 US US07/655,437 patent/US5427958A/en not_active Expired - Fee Related
- 1990-04-23 DE DE69006306T patent/DE69006306T2/en not_active Expired - Fee Related
- 1990-04-23 WO PCT/FR1990/000288 patent/WO1990012806A1/en active IP Right Grant
-
1995
- 1995-04-07 US US08/418,435 patent/US5545718A/en not_active Expired - Fee Related
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KR20030042944A (en) * | 2001-11-26 | 2003-06-02 | 주식회사 인투젠 | Identification of systemic lupus erythematosus(sle)-specific markers and their uses |
WO2003086273A2 (en) * | 2002-04-08 | 2003-10-23 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Histone conjugates and uses thereof |
WO2003086273A3 (en) * | 2002-04-08 | 2004-08-26 | Yissum Res Dev Co | Histone conjugates and uses thereof |
US20060008464A1 (en) * | 2002-04-08 | 2006-01-12 | Chaim Gilon | Histone conjugates and uses thereof |
WO2011151826A3 (en) * | 2010-06-01 | 2012-03-29 | Ben-Gurion University Of The Negev Research And Development Authority | An expeditious synthesis of ubiquitinated peptide conjugates |
US20130143251A1 (en) * | 2010-06-01 | 2013-06-06 | Ben-Gurion University Of The Negev Research And Development Authority | Expeditious synthesis of ubiquitinated peptide conjugates |
CN114456275A (en) * | 2022-01-27 | 2022-05-10 | 苏州大学 | Synthetic method of multi-site single ubiquitin modified histone |
Also Published As
Publication number | Publication date |
---|---|
EP0423301A1 (en) | 1991-04-24 |
DE69006306T2 (en) | 1994-08-04 |
DE69006306D1 (en) | 1994-03-10 |
EP0423301B1 (en) | 1994-01-26 |
FR2646425B1 (en) | 1991-08-30 |
WO1990012806A1 (en) | 1990-11-01 |
FR2646425A1 (en) | 1990-11-02 |
US5545718A (en) | 1996-08-13 |
JPH03505590A (en) | 1991-12-05 |
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